1,2-Ethylene Dichloride Tier I Program Review Testing; Notice of
Availability and Solicitation of Comment
[Federal Register: September 5, 2006 (Volume 71, Number 171)]
[Notices]
[Page 52329-52333]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05se06-30]
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ENVIRONMENTAL PROTECTION AGENCY
[EPA-HQ-OPPT-2003-0010; FRL-8088-3]
1,2-Ethylene Dichloride Tier I Program Review Testing; Notice of
Availability and Solicitation of Comment
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: Under section 4 of the Toxic Substances Control Act (TSCA),
EPA issued a testing consent order that incorporated an enforceable
consent agreement (ECA) for 1,2-ethylene dichloride (EDC). The
companies subject to the ECA agreed to conduct toxicity testing,
develop a computational dosimetry model for route-to-route
extrapolations, and develop pharmacokinetics and mechanistic testing
data that are intended to satisfy the toxicological data needs for EDC
identified in a TSCA section 4 proposed test rule for a number of
hazardous air pollutant chemicals. This notice announces that EPA is
starting the program review component of the EDC ECA alternative
testing program, and solicits comment on data received under the Tier I
Program Review Testing segment of the EDC ECA. Comments are expected to
inform EPA's decision on whether data and computational dosimetry model
development completed by the test sponsors are sufficient to proceed
with the Tier II Testing and computational dosimetry modeling for
route-to-route extrapolations listed in the EDC ECA.
DATES: Comments must be received on or before October 5, 2006.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPPT-2003-0010, by one of the following methods:
? Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
? Mail: Document Control Office (7407M), Office of Pollution
Prevention and Toxics (OPPT), Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460-0001.
? Hand Delivery: OPPT Document Control Office (DCO), EPA
East, Rm. 6428, 1201 Constitution Ave., NW., Washington, DC. Attention:
Docket ID Number EPA-HQ-OPPT-2003-0010. The DCO is open from 8 a.m. to
4 p.m., Monday through Friday, excluding legal holidays. The telephone
number for the DCO is (202) 564-8930. Such deliveries are only accepted
during the DCO's normal hours of operation, and special arrangements
should be made for deliveries of boxed information.
Instructions: Direct your comments to docket ID number EPA-HQ-OPPT-
2003-0010. EPA's policy is that all comments received will be included
in the public docket without change and may be made available on-line
at http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information for which
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system,
which means EPA will not know your identity or contact information
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov,
your e-mail address will be automatically captured and included as part
of the comment that is placed in the public docket and made available
on the Internet. If you submit an electronic comment, EPA recommends
that you include your
[[Page 52330]]
name and other contact information in the body of your comment and with
any disk or CD ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses.
Docket: All documents in the docket are listed in the
regulations.gov index. Although listed in the index, some information
is not publicly available, e.g., CBI or other information for which
disclosure is restricted by statute. Certain other material, such as
copyrighted material, will be publicly available only in hard copy.
Publicly available docket materials are available either electronically
at http://www.regulations.gov, or in hard copy at the OPPT Docket, EPA
Docket Center (EPA/DC), EPA West, Rm. B102, 1301 Constitution Ave.,
NW., Washington, DC. The Public Reading Room is open from 8:30 a.m. to
4:30 p.m., Monday through Friday, excluding legal holidays. The
telephone number of the Public Reading Room is (202) 566-1744, and the
telephone number for the OPPT Docket is (202) 566-0280.
FOR FURTHER INFORMATION CONTACT: For general information contact: Colby
Lintner, Regulatory Coordinator, Environmental Assistance Division
(7408M), Office of Pollution Prevention and Toxics, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (202) 554-1404; e-mail address:
TSCA-Hotline@epa.gov.
For technical information contact: Richard Leukroth or John
Schaeffer, Chemical Control Division (7405M), Office of Pollution
Prevention and Toxics, Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number:
(202) 564-8157; e-mail address: ccd.citb@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the public in general, and may be of
particular interest to those persons who are or may be required to
conduct testing of chemical substances under TSCA. Since other entities
may also be interested, the Agency has not attempted to describe all
the specific entities that may be affected by this action. If you have
any questions regarding the applicability of this action to a
particular entity, consult either technical person listed under FOR
FURTHER INFORMATION CONTACT.
B. What Should I Consider as I Prepare My Comments for EPA?
1. Technical and scientific considerations. EPA invites interested
parties to provide views on the test sponsors' Tier I Program Review
Testing reports entitled: 1,2-Dichloroethane (EDC): Limited
Pharmacokinetics and Metabolism Study in Fischer 344 Rats and
Physiologically Based Pharmacokinetic Model Development and Simulations
for Ethylene Dichloride (1,2-Dichloroethane) in Rats (Refs. 1 and 2).
These reports describe a computational dosimetry model for route-to-
route extrapolation and development of pharmacokinetics and mechanistic
data (PK/MECH data) that will support the use of this model for
quantitative route-to-route extrapolations specific to endpoints listed
under Tier II of the EDC ECA. The computational dosimetry model and PK/
MECH data described in these reports, if deemed acceptable to EPA, will
be applied to support the EDC ECA Tier II Testing and computational
dosimetry model extrapolation reporting called for under Tier II of the
EDC ECA. EPA is interested in comments on the PK/MECH data, the EDC
computational dosimetry model for route-to-route extrapolation, and the
utility of resulting derived computational data from the EDC
computational dosimetry model that will be developed under Tier II of
the EDC ECA.
2. Submitting CBI. Do not submit CBI to EPA through regulations.gov
or e-mail. Clearly mark the part or all of the information that you
claim to be CBI. For CBI information contained in a disk or CD ROM that
you mail to EPA, mark the outside of the disk or CD ROM as CBI and then
identify electronically within the disk or CD ROM the specific
information that is claimed CBI. In addition to one complete version of
the comment that includes information claimed as CBI, a copy of the
comment that does not contain the information claimed as CBI must be
submitted for inclusion in the public docket. Information so marked
will not be disclosed except in accordance with procedures set forth in
40 CFR part 2.
3. Tips for preparing your comments. When submitting comments,
remember to:
i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
ii. Follow directions. As discussed in Unit I.B.1., the Agency asks
you to respond to specific questions regarding the EDC ECA program review.
iii. Explain why you agree or disagree with the materials under
consideration for the EDC ECA program review; provide a convincing
argument for your views or offer alternative ways to improve the science.
iv. Describe any assumptions and provide any technical information
and/or data that you used.
v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
vi. Provide specific examples to illustrate your concerns and
suggested alternatives.
vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
viii. Make sure to submit your comments by the comment period
deadline identified.
II. Background
A. What Testing is EPA Requiring for EDC?
EPA proposed health effects testing under TSCA section 4(a) for a
number of hazardous air pollutants (HAPs or HAP chemicals), including
EDC, in the Federal Register of June 26, 1996 (Ref. 3), as amended
(Refs. 4 and 5). The testing needs for EDC identified in the HAPs
proposed rule, as amended, are acute toxicity, subchronic toxicity,
developmental toxicity, reproductive toxicity, and neurotoxicity (acute
and subchronic), to be conducted by the inhalation route of exposure.
In that proposed TSCA section 4(a) rule, EPA also invited the
submission of proposals that could use the performance of PK studies
and computional dosimetry modeling to permit extrapolation from oral
data to predict risk from inhalation exposure. Such proposals could
provide the scientific basis for alternative testing to the testing
proposed under the rule and form the basis for developing needed HAPs
data via ECAs (Refs. 3, 4, and 5).
On November 22, 1996, Dow Chemical Company, Vulcan Materials
Company, Occidental Chemical Corporation, Oxy Vinyls, LP, Georgia Gulf
Corporation, Westlake Chemical Corporation, PPG Industries, Inc., and
Formosa Plastics Corporation, U.S.A. (the Companies), under the
auspices of the HAP Task Force (the principal testing sponsor),
submitted a proposal for alternative testing of EDC that included
physiologically based pharmacokinetics (PBPK) studies and computational
dosimetry model development to support route-to-route
[[Page 52331]]
extrapolation of testing to be conducted under the ECA by the oral
route (Ref. 6). EPA considered this proposal sufficient (Ref. 7) to
enter into ECA negotiations with the Companies and other interested
parties (Ref. 8). The ECA for EDC was announced in the Federal Register
of June 3, 2003 (Ref. 9). Under the EDC ECA (Ref. 10), the HAPs data
needs for EDC are being addressed via an alternative testing program
that utilizes testing by inhalation and the oral route, computational
dosimetry model development, and development of PK/MECH data to support
route-to-route extrapolation modeling for health effects endpoints
identified in the ECA. EPA anticipates fulfilling all of the health
effects testing requirements identified in the HAPs proposed rule, as
amended, by implementation of the testing to be performed under the EDC
ECA and Order.
B. How is EPA Implementing Testing for EDC Under the ECA?
The EDC ECA alternative testing program has four segments, as
follows: Tier I HAPs Testing, Tier I Program Review Testing, EPA
Program Review, and Tier II Testing and/or Extrapolation Reporting.
1. Tier I HAPs Testing. The ECA testing and reporting requirements
for Tier I HAPs Testing have been completed. Under this segment of the
EDC ECA, the Companies performed endpoint testing for acute toxicity,
with bronchoalveolar lavage (BAL) and histopathology, and acute
neurotoxicity (Ref. 11). These studies were conducted under a combined
protocol by inhalation exposure. The ECA acknowledged that macrophage
function testing (a component of EPA's acute toxicity test guideline 40
CFR 799.9135) is adequately fulfilled by existing data published by
Sherwood et al. (1987; Ref. 12) and also acknowledged that the
developmental studies reported by Rao et al. (1980; Ref. 13), in
rabbits, and Payan et al. (1995; Ref. 14) in rats, adequately fulfill
the HAPs rulemaking testing requirements for developmental toxicity
testing for EDC.
2. Tier I Program Review Testing. The ECA testing and reporting
requirements for Tier I Program Review Testing have been completed.
Under this segment of the EDC ECA the Companies conducted studies to
extend the computational dosimetry model of D'Souza et al. (1987, 1988;
Refs. 15 and 16) in order to apply the model to the specific health
effects endpoints for EDC listed in the ECA, validate the model, and
verify the model's ability to perform quantitative route-to-route
extrapolations of dose response. The ECA provided for the development
of PK/MECH data to support the application of the computational
dosimetry model for the endpoints listed under Tier II of the EDC ECA.
The Companies also provided model simulations with point and
uncertainty estimates of internal dose metrics (parent chemical peak
and area under the curve (AUC) concentrations in blood and brain, and
24-hour total glutathione (GSH)-dependent metabolism in lung and liver)
in rats and humans to inform quantitative route-to-route extrapolations
of the EDC dose response. Furthermore, based on an additional analysis
of the D'Souza et al. model, the ECA was modified to include the kidney
in the examination of GSH-dependent metabolism (Refs. 17, 18, and 19).
Information derived from the GSH-metabolism, PK/MECH data, and model
simulations will be used to evaluate the acceptability of performing:
i. Oral-to-inhalation extrapolation of subchronic toxicity data
reported by Daniel, et al. (1994; Ref. 20) relevant to corn oil gavage.
ii. Oral-to-inhalation extrapolation of subchronic neurotoxicity
data relevant to drinking water exposure of a study to be conducted
under Tier II Testing.
iii. Oral-to-inhalation extrapolation of reproductive effects
testing conducted under Tier II Testing and each dosing paradigm of
studies reported by Alumot et al. (1976; Ref. 21), Rao et al. (1980,
Ref. 13), and Lane et al. (1982; Ref. 22).
3. EPA Program Review. As indicated in Unit VI.C. of the EDC ECA
and Unit II.B.3. of this notice, computational dosimetry model
development and data from Tier I Program Review Testing are subject to
an EPA Program Review. The EPA Program Review will determine whether
the computational dosimetry model and the PK/MECH data used to support
the route-to-route extrapolations of dose response are scientifically
sound and provide the highest quality data. Specifically, as described
in Unit VII. of the EDC ECA, the EPA Program Review will determine:
i. Whether it is feasible and appropriate to apply Tier I Program
Review Testing data and data from other studies acceptable to EPA to
support computational route-to-route extrapolations of dose response
for any or all of the endpoints listed in the Tier II Testing segment
of the ECA, including endpoint data from extant studies cited in the
EDC ECA;
ii. Whether the data from the Tier I Program Review Testing segment
provide a sufficient basis for conducting the endpoint testing and/or
the computational route-to-route extrapolations for the dose responses
specified in the Tier II Testing segment; and/or
iii. The nature and scope of any additional work (e.g., development
of additional PK/MECH data, modification to the EDC computational
dosimetry model) that may be required to support Tier II Testing and
application of the EDC computational dosimetry model for route-to-route
extrapolation of dose-response reporting for the testing endpoints
listed under Tier II of the EDC ECA.
4. Tier II Testing and/or Extrapolation Reporting. This segment of
the EDC ECA alternative testing program will consist of endpoint
testing by drinking water exposure for subchronic neurotoxicity and
reproductive toxicity. The reproductive effects toxicity testing is
intended to confirm studies reported by Alumot et al. (1976; Ref. 21),
Rao et al. (1980; Ref. 13), and Lane et al. (1982; Ref. 22), and
provide data needed on fertility index, gestation index, gross
necropsy, organ weight, histopathology, estrous cycle, sperm
evaluation, vaginal opening, and preputial separation as described in
the ECA. This segment will also include application of the EDC
computational dosimetry model for quantitative route-to-route
extrapolation reporting (oral to inhalation) for Tier II endpoint
testing (subchronic neurotoxicity and reproductive toxicity) and
similar computational extrapolation reporting for extant subchronic
toxicity reported by Daniel et al. (1994; Ref. 20).
III. What Action is the Agency Taking?
A. What Opportunity is There for Public Involvement in EPA's Program
Review?
Tier I HAPs Testing for EDC is completed and reports for Tier I
Program Review Testing have been submitted by the Companies. Copies of
these submissions are available in the public docket (EPA-HQ-OPPT-2003-
0010). As described in Unit II.B.3. and stated in Part VI. of the EDC
ECA, the next step is for EPA to conduct a Program Review on the data
collected from the Tier I Program Review Testing segment of the EDC ECA
alternative testing program. As noted in Unit I.B., this notice of
availability and request for written comments provides an opportunity
for public comment on reports subject to this EPA Program Review.
B. What Happens at the Conclusion of EPA's Program Review?
A description of the possible outcomes of the EPA Program Review is
provided in Part VII. of the EDC ECA. Following the EPA Program Review,
EPA will place in the public docket for
[[Page 52332]]
this action (under docket ID number EPA-HQ-OPPT-2003-0010) a copy of
each comment received, and a copy of the letter informing the HAP Task
Force of the outcome from EPA's Program Review. EPA will publish a
Federal Register notice which announces the availability of a report
describing the findings and conclusions of the Program Review, responds
to comments on the Tier I Program Review Testing, identifies any
modifications to Tier II ECA activities, and establishes revised
deadlines as needed for completion of Tier II Testing and route-to-
route computational dosimetry modeling for extrapolations listed under
Tier II of the ECA for EDC.
IV. Materials in the Docket
The docket for this document has been established under docket ID
number EPA-HQ-OPPT-2003-0010. The public docket is available for review
as specified in ADDRESSES. The following is a listing of the documents
referenced in this preamble that have been placed in the public docket
for this document:
1. HAP Task Force. Letter from Peter E. Voytek to the Document
Control Office with attachment entitled: 1,2-Dichloroethane (EDC):
Limited Pharmacokinetics and Metabolism Study in Fischer 344 Rats.
March 2, 2006. (See Document ID No. EPA-HQ-OPPT-2003-0010-0081 (for
letter) and Document ID No. EPA-HQ-OPPT-2003-0010-0082 (for attachment)).
2. HAP Task Force. Letter from Peter E. Voytek to the Document
Control Office with attachment entitled: Physiologically Based
Pharmacokinetic Model Development and Simulations for Ethylene
Dichloride (1,2-Dichloroethane) in Rats. July 7, 2006. (See Document ID
No. EPA-HQ-OPPT-2003-0010-0086).
3. EPA. Proposed Test Rule for Hazardous Air Pollutants. Proposed
Rule. Federal Register (61 FR 33178, June 26, 1996) (FRL-4869-1).
Available on-line at http://www.epa.gov/fedrgstr/.
4. EPA. Amended Proposed Test Rule for Hazardous Air Pollutants;
Extension of Comment Period. Proposed Rule. Federal Register (62 FR
67466, December 24, 1997) (FRL-5742-2). Available on-line at
http://www.epa.gov/fedrgstr/.
5. EPA. Amended Proposed Test Rule for Hazardous Air Pollutants;
Extension of Comment Period. Proposed Rule. Federal Register (63 FR 19694,
April 21, 1998) (FRL-5780-6). Available on-line at
http://www.epa.gov/fedrgstr/.
6. HAP Task Force. Letter from Peter E. Voytek to the Document
Control Office with attachment entitled: Proposal for Pharmacokinetics
Study of Ethylene Dichloride, November 22, 1996. November 22, 1996.
(See Document ID No. EPA-HQ-OPPT-2003-0010-0034).
7. EPA. Letter from Charles M. Auer to Peter E. Voytek with
attachment entitled: Preliminary EPA Technical Analysis of Proposed
Industry Pharmacokinetics (PK) Strategy for Ethylene Dichloride, June,
1997. June 26, 1997. (See Document ID No. EPA-HQ-OPPT-2003-0010-0035).
8. EPA. Enforceable Consent Agreement Development for Ethylene
Dichloride; Solicitation of Interested Parties and Notice of Public
Meeting. Notice. Federal Register (62 FR 6626, December 19, 1997) (FRL-
5763-1). Available on-line at http://www.epa.gov/fedrgstr/.
9. EPA. 1,2-Ethylene Dichloride; Final Enforceable Consent
Agreement and Testing Consent Order. Notice. Federal Register (68 FR
33125, June 3, 2003) (FRL-7300-6). Available on-line at
http://www.epa.gov/fedrgstr/.
10. EPA. Enforceable Consent Agreement for 1,2-Ethylene Dichloride.
May 15, 2003. (CAS No. 107-06-2) (See Document ID No. EPA-HQ-OPPT-2003-
0010-0002).
11. HAP Task Force. Letter from Peter E. Voytek to the Document
Control Office with attachment entitled: 1,2-Dichloroethane (EDC):
Acute Inhalation Toxicity with Bronchoalveolar Lavage and
Histopathology/Acute Inhalation Neurotoxicity Study in F344/DUCRL Rats.
June 21, 2006. (See Document ID Nos. EPA-HQ-OPPT-2003-0010-0087 through
EPA-HQ-OPPT-2003-0010-0087.6).
12. Sherwood, R.L.; O'Shea, W.; Thomas, P.T.; Ratajczak, H.V.; and
Aranyi, C. Effects of inhalation of ethylene dichloride on pulmonary
defenses of mice and rats. Toxicology and Applied Pharmacology 91: 491-
496 (1987).
13. Rao, K.S.; Murray, J.S.; Deacon, M.M.; John, J.A.; Calhoun,
L.L.; and Young, J.T. Teratogenicity and reproduction studies in
animals inhaling ethylene dichloride. Banbury Report 5: 149-166 (1980).
14. Payan, J.P.; Saillenfait, A.M.; Bonnet, P.; Fabry, J.P.;
Langonne, I.; and Sabate J.P. Assessment of the developmental toxicity
and placental transfer of the 1,2-dichloroethane in rats. Fundamental
and Applied Toxicology 28: 187-198 (1995).
15. D'Souza, R.W.; Francis, W.R.; Bruce R.D.; and Andersen, M.E.
Physiologically based pharmacokinetic model for ethylene dichloride and
its application in risk assessment, pp 286-301. Pharmacokinetics in
Risk Assessment. National Academy Press. Washington, DC (1987).
16. D'Souza, R.W.; Francis, W.R.; and Andersen, M.E. Physiological
model for tissue glutathione depletion and increased resynthesis after
ethylene dichloride exposure. Journal of Pharmacology and Experimental
Therapeutics 245(2): 563-568 (1988).
17. EPA. Letter dated March 24, 2004 from Wardner G. Penberthy to
Peter E. Voytek with two attachments entitled:
i. Addendum Modification to Enforceable Consent Agreement for
1,2,Ethylene Dichloride (EDC).
ii. Application of a PBPK model for cancer and non-cancer risk
assessment of 1,2-dicholoroethane. Phase I: Evaluation of issues
related to the use of a PBPK model for DCE. Requisition Reference No.
2WE59, QT-DC-030387.
(See Document ID Nos. EPA-HQ-OPPT-2003-0010-0059 (for letter) and EPA-
HQ-OPPT-2003-0010-0060 (for attachments)).
18. HAP Task Force. Letter from Peter E. Voytek to the Document
Control Office Re: Testing Consent Order for Ethylene Dichloride;
Request for Modification of Enforceable Consent Agreement. June 21,
2004. (See Document ID No. EPA-HQ-OPPT-2003-0010-0063).
19. EPA. Letter dated July 14, 2004 from Wardner G. Penberthy to
Peter E. Voytek RE: 1,2-Ethylene Dichloride (EDC), Request for
Modification of PBPK Testing in Tier I Testing of the EDC ECA. (See
Document ID No. EPA-HQ-OPPT-2003-0010-0065).
20. Daniel, F.B.; Robinson, M.; Olson, G.R.; York, R.G.; and
Condie, L.W. Ten and ninety-day toxicity studies of 1,2-dichloroethane
in Sprague-Dawley rats. Drug and Chemical Toxicology 17: 463-477 (1994).
21. Alumot, E.; Nachtomi, E.; Mandel, E.; Holstein, P.; Bondi, A.;
and Herzberg, M. Tolerance and acceptable daily intake of chlorinated
fumigants in the rat diet. Food, Cosmetics and Toxicology 14: 105-110
(1976).
22. Lane, R.W.; Riddle, B.L.; and Borzelleca, J.F. Effects of 1,2-
dichloroethane and 1,1,1-trichloroethane in drinking water on
reproduction and development in mice. Toxicology and Applied
Pharmacology 63: 409-421 (1982).
List of Subjects
Environmental protection, 1,2-Ethylene Dichloride, Hazardous chemicals.
[[Page 52333]]
Dated: August 24, 2006.
Wardner G. Penberthy,
Acting Director, Chemical Control Division, Office of Pollution
Prevention and Toxics.
[FR Doc. E6-14639 Filed 9-1-06; 8:45 am]
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